The disparity in survival among African American (AA) women affected by breast cancer is associated with poorly known clinical and pathological characteristics. A comprehensive molecular approach to understand the biological basis related to the increased mortality and poorer prognosis in this ethnic group is needed to eliminate differences in outcomes among AA patients. We propose to address this need by demonstrating that IGF-II, EFABP and cathepsin D (CD) are associated with the disparity observed in AA breast cancer patients outcome. The hypothesis underlying this proposal is that increased IGF-II and cathepsin D caused by oxidative stress and lack of EFABP promotes rapid tumor growth and metastasis resulting in a survival disparity. The specific aims of the proposal are: 1) Demonstrate that higher levels of CD and IGF-II are present in normal and breast tumor tissues of AA patients as compared to tissues from Caucasian patients; 2. Demonstrate that CD and IGF-II are highly expressed in breast cancer cells established from AA patients in vitro and that increase in these proteins promotes rapid tumor growth and metastasis in an animal model in vivo;3. Demonstrate that the expression of EFABP is reduced in normal tissues from AA breast cancer patients as compared to tissues from Caucasian patients.Our purpose is to demonstrate that higher levels of IGF-II and cathepsin D are present in paired tissues from AA breast cancer patients and that their expression correlates with decreased survival. We will further test our hypothesis in vitro and in vivo. Analysis in vitro of the breast cancer cells established from AA patients will allow us to identify the specific forms of IGF-II and CD secreted by these cells as compared to forms secreted from cells from Caucasian patients. Higher molecular forms of IGF-II and CD are associated with glycosylation and are more potent in promoting tumor progression. The in vivo animal model will allow us to characterize the progression of the disease. Correlation of CD, IGF-II and EFABP with disease progression will provide much needed insight in understanding the mechanisms of how differential expression of these factors may account for the disparity in survival outcomes observed in AA breast cancer patients. The technical objectives, research design, and methods for this proposal will confirm, expand, and extend these preliminary findings. The hypothesis will be supported if these technical objectives are achieved.